This application claims the benefit of foreign priority under 35 U.S.C. xc2xa7119 to German patent application no. 19941764.4-43, filed on Sep. 2, 1999, the contents of which are incorporated by reference herein.
The invention relates to substituted acylguanidines and their pharmaceutically tolerable salts and physiologically functional derivatives.
In addition to a number of factors, the formation of gallstones is essentially determined by the composition of the bile, in particular by the concentration and the ratio of cholesterol, phospholipids and bile salts. A prerequisite for the formation of cholesterol gallstones is the presence of bile which is supersaturated in cholesterol (ref. Carey, M. C. and Small, D. M. (1978) The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man, J. Clin. Invest. 61: 998-1026).
Up to now, gallstones have mainly been removed surgically, so that there is a great therapeutic need for the medicinal dissolution of gallstones and for the prevention of gallstone formation.
The invention was based on the object of making available compounds which are able to prevent the formation of gallstones by preventing the supersaturation of the bile with cholesterol, or by delaying the formation of cholesterol crystals from supersaturated biles.
The invention therefore relates to compounds of the formula I 
in which:
T1 and T2 independently of one another are 
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen;
Z is 
A is a bond, (C1-C4)-alkyl, (C0-C4)-alkyl-X;
X is xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CH[OH]xe2x80x94, xe2x80x94CH[OCH3]xe2x80x94, xe2x80x94SO(0-2)xe2x80x94 or xe2x80x94NHxe2x80x94,xe2x80x94N(CH3)xe2x80x94;
D is phenylene which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, xe2x80x94CF3, (C1-C4)-alkyl, hydroxyl, methoxy, xe2x80x94NH2, NHCH3, N(CH3)2, CH3SO2xe2x80x94 and H2NO2Sxe2x80x94;
R(A), R(B), R(C), R(D), R(E), R(F) independently of one another are hydrogen, F, Cl, Br, I, CN, OH, OR(6), NR(7)R(8), (C1-C8)-alkyl, Oxe2x80x94(C1-C12)-alkyl, (C3-C8)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(6) is (C3-C6)-alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy, NR(9)R(10);
R(9), R(10) independently of one another are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8) independently of one another are (C1-C4)-alkyl, (C3-C6)-alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy, NR(9)R(10); or
R(7) and R(8) together form a chain of 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, sulfur, NH, Nxe2x80x94CH3 or N-benzyl;
s is zero or 1,
x is zero, 1 or 2;
y is zero, 1 or 2;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, Br, I, CN, xe2x80x94(Cxe2x95x90O)xe2x80x94Nxe2x95x90C(NH2)2, xe2x80x94SO(0-1)xe2x80x94(C1-C8)-alkyl, Oxe2x80x94(C0-C4)xe2x80x94alkylphenyl, xe2x80x94(C0-C4)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy, xe2x80x94(C0-C4)-alkyl-NR(21)R(22);
(C1-C8)-alkyl, Oxe2x80x94(C1-C12)-alkyl, (C3-C8)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(21), R(22) independently of one another are H, (C1-C4)-alkyl;
L is (C1-C15)-alkyl, it being possible for one or more (CH2) groups to be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR(47)xe2x80x94, xe2x80x94NR(48)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94;
R(47) is hydrogen, (C1-C8)-alkyl, R(48)xe2x80x94COxe2x80x94, phenyl, benzyl;
R(48) is hydrogen, (C1-C8)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
R(40) to R(45) independently of one another are H, xe2x80x94O R(50), xe2x80x94S R(50), NH R(50), xe2x80x94N R(50)2, xe2x80x94Oxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94Sxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94NHxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94Oxe2x80x94POxe2x80x94(O R(50))xe2x80x94O R(50), xe2x80x94Oxe2x80x94(SO2)xe2x80x94O R(50), xe2x80x94R(50), a bond to L; or
R(40) and R(41), R(42) and R(43), R(44) and R(45) in each case together are the oxygen of a carbonyl group;
just one of the radicals always having the meaning of a bond to L;
R(50) is hydrogen, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
K is xe2x80x94OR(51), xe2x80x94NH(R51), xe2x80x94N(R51)2, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94SO3H, xe2x80x94N(CH3)CH2CO2H, xe2x80x94HNxe2x80x94CH(R46)CO2H, xe2x80x94OKa, Ka being a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R(46) is hydrogen, C1-C4-alkyl, benzyl, xe2x80x94CH2xe2x80x94OH, H3CSCH2CH2xe2x80x94, HO2CCH2xe2x80x94, HO2CCH2CH2xe2x80x94;
R(51) is H, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl radical to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
and their pharmaceutically tolerable salts and physiologically functional derivatives.
Preferred compounds are those of the formula I 
in which one or more radical(s) has or have the following meaning:
T1 and T2 independently of one another are equal to 
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen,
Lxe2x80x94Z is 
A is a bond, xe2x80x94CH2xe2x80x94, CH2xe2x80x94Xxe2x80x94;
X is xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CH[OH]xe2x80x94, xe2x80x94CH[OCH3]xe2x80x94, xe2x80x94SO(0-2)xe2x80x94 or xe2x80x94NHxe2x80x94, N(CH3)xe2x80x94;
s is zero or 1;
D is phenylene which can be up to disubstituted by F, Cl, xe2x80x94CF3, (C1-C4)-alkyl, hydroxyl, methoxy, xe2x80x94NH2, NHCH3, N(CH3)2, CH3SO2xe2x80x94, H2NO2Sxe2x80x94;
R(E) is F, Cl, CN, OR(12), (C1-C4)-alkyl, Oxe2x80x94(C1-C4)-alkyl, (C3-C6)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(6) is (C3-C6)-alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy, NR(9)R(10);
R(9), R(10) independently of one another are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(F) is hydrogen;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, Br, I, CN, xe2x80x94(Cxe2x95x90O)xe2x80x94Nxe2x95x90C(NH2)2, xe2x80x94SO(0-1)xe2x80x94(C1-C8)-alkyl, Oxe2x80x94(C0-C4)-alkylphenyl, xe2x80x94(C0-C4)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstitued by F, Cl, CF3, methyl, methoxy;
L is (C1-C8)-alkyl, where one or more (CH2) groups can be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR(47)xe2x80x94, xe2x80x94NR(48)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94;
R(47) is hydrogen, (C1-C4)-alkyl, R(48)xe2x80x94COxe2x80x94, phenyl, (CH2)-phenyl;
R(47) is hydrogen, (C1-C4)-alkyl, R(48)-COxe2x80x94, phenyl, (CH2)-phenyl;
R(48) is hydrogen, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible methyl, methoxy;
R(41), R(42), R(45) independently of one another are H, xe2x80x94O R(50), xe2x80x94S R(50), NH R(50), xe2x80x94N R(50)2, xe2x80x94Oxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94Sxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94NHxe2x80x94(CO)xe2x80x94 R(50), xe2x80x94Oxe2x80x94POxe2x80x94(O R(50))xe2x80x94O R(50), xe2x80x94Oxe2x80x94(SO2)xe2x80x94O R(50), xe2x80x94R(50);
R(50) is hydrogen, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl nucleus to be up to trisubstitued by; F, Cl, CF3, methyl, methoxy;
K is xe2x80x94OR(51), xe2x80x94NH(R51), xe2x80x94N(R51)2, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94SO3H, xe2x80x94N(CH3)CH2CO2H, xe2x80x94HNxe2x80x94CH(R46)CO2H, xe2x80x94OKa, Ka being a cation, such as, for example, an alkali metal or an alkaline earth metal ion or a quaternary ammonium ion,
R(46) is H, C1-C4-alkyl, benzyl, xe2x80x94CH2xe2x80x94OH, H3CSCH2CH2xe2x80x94, HO2CCH2xe2x80x94, HO2CCH2CH2xe2x80x94;
R(51) is H, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl radical to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
and their pharmaceutically tolerable salts.
Particularly preferred compounds are those of the formula I 
in which one or more radical(s) has or have the following meaning:
T1 and T2 independently of one another are equal to 
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen,
Lxe2x80x94Z is 
A is a bond, xe2x80x94CH2xe2x80x94, CH2xe2x80x94Xxe2x80x94, xe2x80x94Xxe2x80x94;
X is xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO(0-2)xe2x80x94;
s is zero or 1;
D is phenylene which can be up to disubstituted by F, Cl, xe2x80x94CF3,(C1-C4)-alkyl, hydroxyl, methoxy, xe2x80x94NH2, NHCH3, N(CH3)2, CH3SO2xe2x80x94, H2NO2S;
R(E) is F, (C1-C4)-alkyl, it being possible in the alkyl radical for one, a number or all hydrogens to be replaced by fluorine;
R(F) is hydrogen;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, CN, xe2x80x94SO2xe2x80x94CH3, Oxe2x80x94(C0-C1)-alkylphenyl, xe2x80x94(C0-C1)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
L is (C1-C8)-alkyl, it being possible for one or more (CH2) groups to be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR(47)xe2x80x94, xe2x80x94NR(48)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94;
R(47) is hydrogen, (C1-C4)-alkyl, R(48)xe2x80x94COxe2x80x94, phenyl, (CH2)-phenyl;
R(48) is hydrogen, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
R(41) is hydrogen, xe2x80x94OH;
K is xe2x80x94OR(51), xe2x80x94NH(R51), xe2x80x94N(R51)2, xe2x80x94HNxe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94SO3H, xe2x80x94N(CH3)CH2CO2H, xe2x80x94OKa, Ka being a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R (51)is H, (C1-C4)-alkyl, phenyl, (CH2)-phenyl, it being possible for the phenyl radical to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
and their pharmaceutically tolerable salts.
Very particularly preferred compounds are those of the formula I 
in which one or more radical(s) has or have the following meaning:
T1 and T2 independently of one another are 
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen,
Lxe2x80x94Z is 
A is a bond, xe2x80x94Oxe2x80x94;
s is zero or 1;
D is phenylene which can be up to disubstituted by F, Cl, xe2x80x94CF3, (C1-C4)-alkyl, hydroxyl, methoxy, N(CH3)2, CH3SO2xe2x80x94, H2NO2S;
R(E) is (C1-C4)-alkyl;
R(F) is hydrogen;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, CN, xe2x80x94SO2xe2x80x94CH3, Oxe2x80x94(C0-C1)-alkylphenyl, xe2x80x94(C0-C1)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF3, methyl, methoxy;
L is (C1-C6)-alkyl, it being possible for one or more (CH2) groups to be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR(47)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94;
R(47) is hydrogen, (C1-C4)-alkyl;
R(41) is hydrogen, xe2x80x94OH;
K is xe2x80x94OH, xe2x80x94HNxe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H, xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94SO3H, xe2x80x94N(CH3)CH2CO2H, xe2x80x94OKa, Ka being a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
and their pharmaceutically tolerable salts.
If the compound of the formula I contains one or more asymmetric centers, these can have either the S or R configuration. The compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof.
The double bond geometry of the compounds of the formula I can be either E or Z. The compounds can be present in the mixture as double bond isomers.
The designated alkyl radicals can be either straight-chain or branched.
The invention furthermore relates to a process for the preparation of the compound I (Lxe2x80x94Z=acetylene-bile acid derivative), which comprises reacting a compound of the formula II, 
in which T1, T2, R(1), R(2) and R(3) have the meaning indicated above and G is a functionality which can be replaced by Lxe2x80x94Z, in a manner known to the person skilled in the art with a compound Lxe2x80x94Z of the formula III. The functionality G of the compound having the formula II can have, for example, the meaning of bromine or iodine, as the desired Cxe2x80x94C bond linkage is achieved by Pd(0) catalysis in the manner known to the person skilled in the art. 
The acetylene-bile acid derivatives of the formula III are prepared from suitable bile acid ketones IV according to Scheme 1. These in turn can be prepared from bile acids V according to processes known from the literature or acquired commercially. To this end, lithiumacetylide is added to ketobile acids of type IV analogously to known processes (U.S. Pat. No. 5,641,767). The acetylene-bile acid derivatives III a thus obtained are deprotected, depending on the type of the protective groups used, in a one-pot process, e.g. with X3, X4=Oacyl, or in two steps, e.g. with X3, X4=THP, to give compounds III b. The carboxylic acid function of b can be converted into suitable esters such as, for example, benzyl, p-methoxybenzyl, trimethylsilyl or t-butylesters of type III c according to different known processes. 
In general, alkenoylguanidines I are weak bases and can bind acid with formation of salts. Possible acid addition salts are salts of all pharmacologically tolerable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
The compounds of the formula I are substituted acylguanidines.
The compounds of the formula (I) according to the invention also pass into the hepatobiliary system and therefore act in these tissues. Thus, for example, the absorption of water from the gall bladder is inhibited by inhibition of the apical NHE antiport of subtype 3 of the gall bladder epithelium, which results in dilute bile fluid.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d used here designates that physiologically tolerable derivative of a compound of the formula I according to the invention, e.g. an ester, which on administration to a mammal, such as, for example, man, is able (directly or indirectly) to form a compound of the formula I or an active metabolite thereof.
The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs themselves can be active or inactive.
The compounds according to the invention can also be present in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are included in the scope of the invention and are a further aspect of the invention.
Below, all references to xe2x80x9ccompound(s) according to formula (I)xe2x80x9d relate to compound(s) of the formula (I) as described above, and its/their salts, solvates and physiologically functional derivatives as described herein.
The amount of a compound according to formula (I) which is necessary in order to achieve the desired biological effect is dependent on a number of factors, e.g. on the selected specific compound, the intended use, the manner of administration and the clinical condition of the patient.
In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, e.g. 0.1-10 mg/kg/day. Tablets or capsules can contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically tolerable salts, the abovementioned weight details relate to the weight of the aminopropanol ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) themselves can be used as the compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition. The carrier must of course be tolerable, in the sense that it is compatible with the other constituents of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds according to formula (I), and including one or more hypolipidemic active compounds. The pharmaceutical compositions according to the invention can be prepared according to one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically tolerable vehicles and/or excipients.
Pharmaceutical compositions according to the invention are those which are suitable for oral and peroral (e.g. sublingual) administration, although the most suitable manner of administration in each individual case is dependent on the nature and severity of the condition to be treated and on the type of the compound according to formula (I) used in each case. Sugar-coated formulations and sugar-coated delayed release formulations are also included in the scope of the invention. Acid-resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration can be present in separate units, such as, for example, capsules, cachets, lozenges or tablets which in each case contain a certain amount of the compound according to formula (I); as powders or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. Thus, for example, a tablet can be prepared by compressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be prepared by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent and/or one (a number of) surface-active/dispersing agents in a suitable machine. Shaped tablets can be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound according to formula (I) with a flavoring, customarily sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
List of abbreviations: